Angiogenesis is the process of formation of new blood vessels from existing ones. Angiogenesis is a normal and vital process in growth and development, as well as in pathological conditions. Angiogenesis has been intensively studied over the past several decades because of its fundamental importance in tissue development, vascular diseases, and cancer. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in fetal and embryonal development and formation of the corpus luteum. Post-natal angiogenesis is an important physiological function in the ovary, endometrium, placenta, and in wound healing. Deregulation of angiogenesis plays a major role in many human diseases including diabetic retinopathy, age-related macular degeneration, endometriosis, atherogenesis, arthritis, psoriasis, corneal neovascularization, rheumatoid arthritis, tumorigenesis, and metastasis, among others.
Tumor angiogenesis involves the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. Angiogenesis is also an element of metastasis of a tumor. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. It has even been suggested that the blood vessels in a solid tumor may in fact be mosaic vessels, comprised of both endothelial cells and tumor cells. Such mosaicity allows for substantial shedding of tumor cells into the vasculature.
It has been shown that there is a direct correlation between tumor microvessel density and the incidence of metastasis. Tumor cells themselves can produce factors that stimulate the proliferation of endothelial cells and new capillary growth. Angiogenesis is important in two stages of tumor metastasis: in vascularization of the tumor, which allows tumor cells to enter the blood stream and to circulate throughout the body; and after the tumor cells have left the primary site and settled into the secondary (metastasis) site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site.
Blockage of angiogenesis is recognized as one of the most promising strategies against cancer (including metastases), retinopathy and endometriosis, among other diseases. A significant increase in the research effort in the angiogenesis field over the past decade has resulted in a substantial increased understanding of the angiogenic process and subsequently the development of new therapeutics to modulate angiogenesis. Because of their extended biological half-life, high diffusibility coefficient and cost effective synthesis non-peptidic antiangiogenic small molecules (SMs) are the main focus of pharmaceutical companies and academic institutions.
Angiogenesis-based anti-tumor therapies typically use natural and synthetic angiogenesis inhibitors such as angiostatin, endostatin and tumstatin. Recently the Food and Drug Administration (FDA) approved an antibody therapy targeting angiogenesis in colorectal cancer. This therapy is based on a monoclonal antibody directed against an isoform of VEGF and is marketed under the trade name Avastin®. The pharmaceutical industry has focused in the development tyrosine kinase inhibitors and tubulin binders as antiangiogenic small molecules. Thus, a need exists for small molecules which exploit other angiogenesis pathways.